rs10262966

Positions:

• chr7-75954007-A-G
• chr7-75954007-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001395413.1(POR):​c.6A>G​(p.Gly2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,598,424 control chromosomes in the GnomAD database, including 3,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1481 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1595 hom.)
• Consequence: POR NM_001395413.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 0.424

Genes affected

POR (HGNC:9208): (cytochrome p450 oxidoreductase) This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-75954007-A-G is Benign according to our data. Variant chr7-75954007-A-G is described in ClinVar as [Benign]. Clinvar id is 16913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.424 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1	c.6A>G	p.Gly2=	synonymous_variant	2/16	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.6A>G	p.Gly2=	synonymous_variant	2/16	1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12131 AN: 152128 Hom.: 1468 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.0602

GnomAD3 exomes AF: 0.0311 AC: 7013 AN: 225548 Hom.: 586 AF XY: 0.0297 AC XY: 3628 AN XY: 121964

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.0715

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0150 AC: 21765 AN: 1446178 Hom.: 1595 Cov.: 31 AF XY: 0.0160 AC XY: 11471 AN XY: 717982

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.00929

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.0699

Gnomad4 FIN exome AF: 0.00657

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0801 AC: 12198 AN: 152246 Hom.: 1481 Cov.: 32 AF XY: 0.0792 AC XY: 5898 AN XY: 74466

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0763

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0203 Hom.: 396

Bravo AF: 0.0892

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17440066) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.9
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10262966; hg19: chr7-75583325;